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- EMDB-67624: Cryo-EM structure of the human P2X3 receptor in the ATP- and sivo... -

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Basic information

Entry
Database: EMDB / ID: EMD-67624
TitleCryo-EM structure of the human P2X3 receptor in the ATP- and sivopixant-bound closed state
Map data
Sample
  • Complex: human P2X3 trimer
    • Protein or peptide: P2X purinoceptor 3
  • Ligand: Sivopixant
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
KeywordsP2X3 / TRANSPORT PROTEIN
Function / homology
Function and homology information


Platelet homeostasis / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / Elevation of cytosolic Ca2+ levels / protein homotrimerization / cellular response to ATP / positive regulation of calcium ion transport into cytosol / positive regulation of calcium-mediated signaling / hippocampal mossy fiber to CA3 synapse / modulation of chemical synaptic transmission ...Platelet homeostasis / extracellularly ATP-gated monoatomic cation channel activity / purinergic nucleotide receptor activity / Elevation of cytosolic Ca2+ levels / protein homotrimerization / cellular response to ATP / positive regulation of calcium ion transport into cytosol / positive regulation of calcium-mediated signaling / hippocampal mossy fiber to CA3 synapse / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / calcium ion transmembrane transport / transmembrane transport / signaling receptor complex / postsynapse / axon / signal transduction / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
P2X3 purinoceptor / : / : / ATP P2X receptors signature. / ATP P2X receptor / P2X purinoreceptor / P2X purinoreceptor extracellular domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsHattori M / Zhao Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: PLoS Biol / Year: 2026
Title: Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant.
Authors: Zhixuan Zhao / Dong-Ping Wang / Xin Zhang / Yuan Gao / Hexin Xu / Xinyu Teng / Cheng Shen / Jirui Chen / Jinru Zhang / Chang-Run Guo / Motoyuki Hattori /
Abstract: P2X receptors are ATP-gated cation channels, and the P2X3 subtype plays crucial roles in peripheral sensory neurons, including in chronic pain and chronic cough. Accordingly, P2X3 receptors have ...P2X receptors are ATP-gated cation channels, and the P2X3 subtype plays crucial roles in peripheral sensory neurons, including in chronic pain and chronic cough. Accordingly, P2X3 receptors have attracted substantial interest as a therapeutic target. Gefapixant, a negative allosteric modulator (NAM) of P2X3 receptors, has been approved in some countries for the treatment of chronic cough; however, its limited selectivity for P2X3 homomers over P2X2/P2X3 heteromers is associated with taste disturbance as a prominent adverse effect. These limitations have motivated the development of next-generation NAMs with improved subtype selectivity, but their subtype-specific allosteric inhibition mechanisms are unclear. Here, we report the cryo-EM structure of the human P2X3 receptor in complex with ATP and the P2X3-selective next-generation NAM sivopixant, an investigational drug. Sivopixant binds to an allosteric site at the portal of the central pocket in the extracellular domain, and structure-based mutational analysis by electrophysiology identifies key residues required for sivopixant-dependent inhibition of human P2X3 receptors. Structural comparisons across P2X subtypes, together with patch-clamp analyses of gain-of-function mutants that confer sensitivity to two investigational drugs, sivopixant and camlipixant, provided a broadly applicable structural framework for subtype selectivity. Furthermore, structural comparisons with apo and ATP-bound open states of P2X3 receptors, together with molecular dynamics simulations, revealed that sivopixant expands the upper-body domain to suppress the lower-body movements required for channel activation, thereby preventing channel opening even in the presence of ATP.
History
DepositionDec 11, 2025-
Header (metadata) releaseApr 1, 2026-
Map releaseApr 1, 2026-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_67624.png

Downloads & links

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Map

FileDownload / File: emd_67624.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 288 pix.
= 276.192 Å		0.96 Å/pix.
x 288 pix.
= 276.192 Å		0.96 Å/pix.
x 288 pix.
= 276.192 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.959 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.2734595 - 0.6938353
Average (Standard dev.)0.0005029255 (±0.014666029)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 276.192 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_67624_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #2

Fileemd_67624_half_map_2.map
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Histogram

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Sample components

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Entire : human P2X3 trimer

EntireName: human P2X3 trimer
Components
  • Complex: human P2X3 trimer
    • Protein or peptide: P2X purinoceptor 3
  • Ligand: Sivopixant
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: human P2X3 trimer

SupramoleculeName: human P2X3 trimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 110 KDa

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Macromolecule #1: P2X purinoceptor 3

MacromoleculeName: P2X purinoceptor 3 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.645332 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: WTIGIINRVV QLLIISYFVG WVFLHEKAYQ VRDTAIESSV VTKVKGSGLY ANRVMDVSDY VTPPQGTSVF VIITKMIVTE NQMQGFCPE SEEKYRCVSD SQCGPERLPG GGILTGRCVN YSSVLRTCEI QGWCPTEVDT VETPIMMEAE NFTIFIKNSI R FPLFNFEK ...String:
WTIGIINRVV QLLIISYFVG WVFLHEKAYQ VRDTAIESSV VTKVKGSGLY ANRVMDVSDY VTPPQGTSVF VIITKMIVTE NQMQGFCPE SEEKYRCVSD SQCGPERLPG GGILTGRCVN YSSVLRTCEI QGWCPTEVDT VETPIMMEAE NFTIFIKNSI R FPLFNFEK GNLLPNLTAR DMKTCRFHPD KDPFCPILRV GDVVKFAGQD FAKLARTGGV LGIKIGWVCD LDKAWDQCIP KY SFTRLDS VSEKSSVSPG YNFRFAKYYK MENGSEYRTL LKAFGIRFDV LVYGNAGKFN IIPTIISSVA AFTSVGVGTV LCD IILLNF L

UniProtKB: P2X purinoceptor 3

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Macromolecule #2: Sivopixant

MacromoleculeName: Sivopixant / type: ligand / ID: 2 / Number of copies: 3 / Formula: A1E2N
Molecular weightTheoretical: 507.926 Da

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 9 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 3 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5yve

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 71855
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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